A Perspective for Ménière’s Disease: In Silico Investigations of Dexamethasone as a Direct Modulator of AQP2
Abstract
:Highlights:
- AQP2 water permeability is modulated by dexamethasone at physiological concentrations.
- The interaction impacts water fluxes through a direct interaction with the extracellular surface of the aquaporin.
- Key interactions implicate conserved residues of the ar/R constriction.
- New insights on corticosteroids mode of actions in Ménière’s disease treatment.
- The nature of the cations significantly impacts AQP2 water permeability.
1. Introduction
2. Materials and Methods
2.1. Molecular Dynamics Simulations
2.2. Analysis
2.2.1. Water Permeability
2.2.2. Free Energy Profiles
2.2.3. Binding Free Energy and Dissociation Constant
2.2.4. Other Properties
2.2.5. Statistical Analysis
3. Results
3.1. AQP2–DEX Interaction Site
3.2. Impact on the Transport Ability of the Channel
3.2.1. Dexamethasone Has a Significant Impact on AQP2 Water Permeability
3.2.2. Dexamethasone Impacts AQP2 Water Permeability through Its Interaction with the Arginine of the ar/R Constriction
3.2.3. Detailed Impact of Dexamethasone Interaction with AQP2 on the Water Permeability as an Illustration of pf Adjustment with the Dk Constant
3.3. Biological Relevance of the Dexamethasone–AQP2 Interaction
3.3.1. Impact of Cation Nature on the Permeability of AQP2
3.3.2. Interaction of AQP2 with Dexamethasone without Docking
3.3.3. Proposed Molecular Mechanism for Specific Interaction between AQP2 Extracellular Surface and Dexamethasone
4. Conclusions and Discussions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Acknowledgments
Conflicts of Interest
Abbreviations
MD | Ménière’s disease |
EH | endolymphatic hydrops |
AQP2 | aquaporin 2 |
Å | Angströms |
PDB code | Protein Data Bank code |
POPC | 1-Palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine |
TIP3 | transferable intermolecular potential 3 |
mM | milliMolar |
KCl | potassium chloride |
ns | nanoseconds |
pf | permeability coefficient |
nb | number |
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Mom, R.; Robert-Paganin, J.; Mom, T.; Chabbert, C.; Réty, S.; Auguin, D. A Perspective for Ménière’s Disease: In Silico Investigations of Dexamethasone as a Direct Modulator of AQP2. Biomolecules 2022, 12, 511. https://doi.org/10.3390/biom12040511
Mom R, Robert-Paganin J, Mom T, Chabbert C, Réty S, Auguin D. A Perspective for Ménière’s Disease: In Silico Investigations of Dexamethasone as a Direct Modulator of AQP2. Biomolecules. 2022; 12(4):511. https://doi.org/10.3390/biom12040511
Chicago/Turabian StyleMom, Robin, Julien Robert-Paganin, Thierry Mom, Christian Chabbert, Stéphane Réty, and Daniel Auguin. 2022. "A Perspective for Ménière’s Disease: In Silico Investigations of Dexamethasone as a Direct Modulator of AQP2" Biomolecules 12, no. 4: 511. https://doi.org/10.3390/biom12040511